12 results on '"Antonellis, Anthony"'
Search Results
2. A recurrent GARS mutation causes distal hereditary motor neuropathy.
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Lee, Diana C., Meyer‐Schuman, Rebecca, Bacon, Chelsea, Shy, Michael E., Antonellis, Anthony, and Scherer, Steven S.
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AGE factors in disease ,GENETIC techniques ,MOTOR neuron diseases ,GENETIC mutation ,PHENOTYPES ,MUSCLE weakness ,DESCRIPTIVE statistics - Abstract
We found a p.Gly327Arg mutation in GARS in two unrelated women, both of whom had a similar phenotype ‐ motor weakness that began in late childhood, distal weakness in the arms and legs, a motor greater than sensory neuropathy with slowing of motor and not sensory conduction velocities. A de novo mutation was proven in one patient and suspected in the other. The p.Gly327Arg GARS variant did not support yeast growth in a complementation assay, showing that this variant severely impairs protein function. Thus, the p.Gly327Arg GARS mutation causes a distal motor neuropathy. [ABSTRACT FROM AUTHOR] more...
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- 2019
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3. To charge or not to charge: mechanistic insights into neuropathy-associated tRNA synthetase mutations.
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Wallen, Rachel C and Antonellis, Anthony
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AMINOACYL-tRNA , *GENETIC mutation , *TRANSFER RNA , *OLIGOMERS , *NEUROPATHY , *MEDICAL genetics - Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for the first step of protein translation—attaching amino acids to cognate tRNA molecules. Interestingly, ARS gene mutations have been implicated in tissue-specific human diseases, including inherited peripheral neuropathies. To date, five loci encoding an ARS have been implicated in peripheral neuropathy, and alleles at each locus show loss-of-function characteristics. The majority of the phenotypes are autosomal dominant, and each of the implicated enzymes acts as an oligomer, indicating that a dominant-negative effect should be considered. On the basis of current data, impaired tRNA charging is likely to be a central component of ARS-related neuropathy. Future efforts should focus on testing this notion and developing strategies for restoring ARS function in the peripheral nerve. [Copyright &y& Elsevier] more...
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- 2013
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4. Disruption of RAB40AL function leads to MartineProbst syndrome, a rare X-linked multisystem neurodevelopmental human disorder.
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Bedoyan, Jirair Krikor, Schaibley, Valerie M., Weiping Peng, Yongsheng Bai, Mondal, Kajari, Shetty, Amol C., Durham, Mark, Micucci, Joseph A., Dhiraaj, Arti, Skidmore, Jennifer M., Kaplan, Julie B., Skinner, Cindy, Schwartz, Charles E., Antonellis, Anthony, Zwick, Michael E., Cavalcoli, James D., Li, Jun Z., and Martin, Donna M. more...
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DEVELOPMENTAL disabilities ,HUMAN abnormality genetics ,CRANIOFACIAL abnormalities ,GENETICS of deafness ,COGNITION disorders ,GENETIC mutation ,GENETICS - Abstract
Background and aim Martin-Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS. Methods and results Massively parallel sequencing in two affected, related male subjects with MPS identified a RAB40AL (also called RLGP) missense mutation (chrX:102,079,078-102,079,079AC→GA p.D59G; hg18). RAB40AL encodes a small Ras-like GTPase protein with one suppressor of cytokine signalling box. The p.D59G variant is located in a highly conserved region of the GTPase domain between β-2 and β-3 strands. Using RT-PCR, the authors show that RAB40AL is expressed in human fetal and adult brain and kidney, and adult lung, heart, liver and skeletal muscle. RAB40AL appears to be a primate innovation, with no orthologues found in mouse, Xenopus or zebrafish. Western analysis and fluorescence microscopy of GFP-tagged RAB40AL constructs from transiently transfected COS7 cells show that the D59G missense change renders RAB40AL unstable and disrupts its cytoplasmic localisation. Conclusions This is the first study to show that mutation of RAB40AL is associated with a human disorder. Identification of RAB40AL as the gene mutated in MPS allows for further investigations into the molecular mechanism(s) of RAB40AL and its roles in diverse processes such as cognition, hearing and skeletal development. [ABSTRACT FROM AUTHOR] more...
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- 2012
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5. Charcot-Marie-Tooth--Linked Mutant GARS Is Toxic to Peripheral Neurons Independent of Wild-Type GARS Levels.
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Motley, William W., Seburn, Kevin L., Nawaz, Mir Hussain, Miers, Kathy E., Cheng, Jun, Antonellis, Anthony, Green, Eric D., Talbot, Kevin, Xiang-Lei Yang, Fischbeck, Kenneth H., and Burgess, Robert W. more...
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GENETIC research ,CHARCOT-Marie-Tooth disease ,TRANSFER RNA synthetases ,GENETIC mutation ,GENETIC disorders ,GENETICS - Abstract
Charcot-Marie-Tooth disease type 2D (CMT2D) is a dominantly inherited peripheral neuropathy caused by missense mutations in the glycyl-tRNA synthetase gene (GARS). In addition to GARS, mutations in three other tRNA synthetase genes cause similar neuropathies, although the underlying mechanisms are not fully understood. To address this, we generated transgenic mice that ubiquitously over-express wild-type GARS and crossed them to two dominant mouse models of CMT2D to distinguish loss-of-function and gain-of-function mechanisms. Over-expression of wild-type GARS does not improve the neuropathy phenotype in heterozygous Gars mutant mice, as determined by histological, functional, and behavioral tests. Transgenic GARS is able to rescue a pathological point mutation as a homozygote or in complementation tests with a Gars null allele, demonstrating the functionality of the transgene and revealing a recessive loss-of-function component of the point mutation. Missense mutations as transgene-rescued homozygotes or compound heterozygotes have a more severe neuropathy than heterozygotes, indicating that increased dosage of the disease-causing alleles results in a more severe neurological phenotype, even in the presence of a wild-type transgene. We conclude that, although missense mutations of Gars may cause some loss of function, the dominant neuropathy phenotype observed in mice is caused by a dose-dependent gain of function that is not mitigated by over-expression of functional wild-type protein. [ABSTRACT FROM AUTHOR] more...
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- 2011
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6. The Role of Aminoacyl-tRNA Synthetases in Genetic Diseases.
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Antonellis, Anthony and Green, Eric D.
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AMINOACYL-tRNA synthetases , *PROTEIN synthesis , *AMINO acids , *CYTOPLASM , *MITOCHONDRIA , *GENETIC mutation , *GENES - Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for performing the first step of protein synthesis. Specifically, ARSs attach amino acids to their cognate tRNA molecules in the cytoplasm and mitochondria. Recent studies have demonstrated that mutations in genes encoding ARSs can result in neurodegeneration, raising many questions about the role of these enzymes (and protein synthesis in general) in neuronal function. In this review, we summarize the current knowledge of genetic diseases that are associated with mutations in ARS-encoding genes, discuss the potential pathogenic mechanisms underlying these disorders, and point to likely areas of future research that will advance our understanding about the role of ARSs in genetic diseases. [ABSTRACT FROM AUTHOR] more...
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- 2008
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7. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus.
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Malecki, Maciej T., Jhala, Ulupi S., Antonellis, Anthony, Fields, Liz, Doria, Alessandro, Orban, Tihamer, Saad, Mohammed, Warram, James H., Montminy, Marc, and Krolewski, Andrzej S.
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GENETIC mutation ,PROTEINS ,TYPE 2 diabetes - Abstract
The helix-loop-helix (HLH) protein NEUROD1 (also known as BETA2) functions as a regulatory switch for endocrine pancreatic development. In mice homozygous for a targeted disruption of Neurod, pancreatic islet morphogenesis is abnormal and overt diabetes develops due in part to inadequate expression of the insulin gene (Ins2). NEUROD1, following its heterodimerization with the ubiquitous HLH protein E47, regulates insulin gene (INS) expression by binding to a critical E-box motif on the INS promoter. Here we describe two mutations in NEUROD1, which are associated with the development of type 2 diabetes in the heterozygous state. The first, a missense mutation at Arg 111 in the DNA-binding domain, abolishes E-box binding activity of NEUROD1. The second mutation gives rise to a truncated polypeptide lacking the carboxy-terminal trans-activation domain, a region that associates with the co-activators CBP and p300 (refs 3,4). The clinical profile of patients with the truncated NEUROD1 polypeptide is more severe than that of patients with the Arg 111 mutation. Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans. [ABSTRACT FROM AUTHOR] more...
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- 1999
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8. Exclusion of the hepatocyte nuclear factor 4alpha as a candidate gene for late-onset NIDDM linked with chromosome 20q.
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Malecki, Maciej T., Antonellis, Anthony, Casey, Peter, Linong Ji, Wantman, Michael, Warram, James H., Krolewski, Andrzej S., Malecki, M T, Antonellis, A, Casey, P, Ji, L, Wantman, M, Warram, J H, and Krolewski, A S more...
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HEPATOCYTE growth factor , *GENETICS of diabetes , *AGE factors in disease , *CELL receptors , *CHROMOSOMES , *COMPARATIVE studies , *GENE mapping , *GENES , *GENETIC polymorphisms , *GENETICS , *RESEARCH methodology , *MEDICAL cooperation , *GENETIC mutation , *TYPE 2 diabetes , *PHOSPHOPROTEINS , *POLYMERASE chain reaction , *PROTEINS , *REFERENCE values , *RESEARCH , *TRANSCRIPTION factors , *DNA-binding proteins , *GENETIC markers , *EVALUATION research - Abstract
Investigates whether the exclusion of the hepatocyte nuclear factor 4alpha as a candidate for late-onset non-insulin-dependent diabetes mellitus (NIDDM) is linked with chromosome 20q. DNA mutations/polymorphisms in the human HNF-4alpha gene; Absence of DNA sequence differences in the HNF-4alpha gene that could account for the development of diabetes. more...
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- 1998
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9. MARS variant associated with both recessive interstitial lung and liver disease and dominant Charcot-Marie-Tooth disease.
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Rips, Jonathan, Meyer-Schuman, Rebecca, Breuer, Oded, Tsabari, Reuven, Shaag, Avraham, Revel-Vilk, Shoshana, Reif, Shimon, Elpeleg, Orly, Antonellis, Anthony, and Harel, Tamar
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AMINOACYL-tRNA synthetases , *CHARCOT-Marie-Tooth disease , *INTERSTITIAL lung diseases , *GENETIC mutation , *PHENOTYPES , *GENETICS - Abstract
Abstract Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed enzymes responsible for charging tRNA with cognate amino acids during protein translation. Non-canonical functions are increasingly recognized, and include transcription and translation control and extracellular signaling. Monoallelic mutations in genes encoding several ARSs have been identified in axonal Charcot-Marie-Tooth (CMT2) disease, whereas biallelic mutations in ARS loci have been associated with multi-tissue syndromes, variably involving the central nervous system, lung, and liver. We report a male infant of non-consanguineous origin, presenting with successive onset of transfusion-dependent anemia, hypothyroidism, cholestasis, interstitial lung disease, and developmental delay. Whole-exome sequencing (WES) revealed compound heterozygosity for two variants (p.Tyr307Cys and p.Arg618Cys) in MARS , encoding methionyl-tRNA synthetase. Biallelic MARS mutations are associated with interstitial lung and liver disease (ILLD). Interestingly, the p.Arg618Cys variant, inherited from an unaffected father, was previously reported in a family with autosomal dominant late-onset CMT2. Yeast complementation assays confirmed pathogenicity of p.Arg618Cys, yet suggested retained function of p.Tyr307Cys. Our findings underscore the phenotypic variability associated with ARS mutations, and suggest genetic or environmental modifying factors in the onset of monoallelic MARS -associated CMT2. [ABSTRACT FROM AUTHOR] more...
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- 2018
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10. Predicting the pathogenicity of aminoacyl-tRNA synthetase mutations.
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Oprescu, Stephanie N., Griffin, Laurie B., Beg, Asim A., and Antonellis, Anthony
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AMINOACYL-tRNA synthetases , *GENETIC mutation , *PROTEIN synthesis , *AMINO acids , *PHENOTYPES - Abstract
Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes responsible for charging tRNA with cognate amino acids—the first step in protein synthesis. ARSs are required for protein translation in the cytoplasm and mitochondria of all cells. Surprisingly, mutations in 28 of the 37 nuclear-encoded human ARS genes have been linked to a variety of recessive and dominant tissue-specific disorders. Current data indicate that impaired enzyme function is a robust predictor of the pathogenicity of ARS mutations. However, experimental model systems that distinguish between pathogenic and non-pathogenic ARS variants are required for implicating newly identified ARS mutations in disease. Here, we outline strategies to assist in predicting the pathogenicity of ARS variants and urge cautious evaluation of genetic and functional data prior to linking an ARS mutation to a human disease phenotype. [ABSTRACT FROM AUTHOR] more...
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- 2017
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11. Loss-of-Function Alanyl-tRNA Synthetase Mutations Cause an Autosomal-Recessive Early-Onset Epileptic Encephalopathy with Persistent Myelination Defect.
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Simons, Cas, Griffin, Laurie B., Helman, Guy, Golas, Gretchen, Pizzino, Amy, Bloom, Miriam, Murphy, Jennifer L.P., Crawford, Joanna, Evans, Sarah H., Topper, Scott, Whitehead, Matthew T., Schreiber, John M., Chapman, Kimberly A., Tifft, Cyndi, Lu, Katrina B., Gamper, Howard, Shigematsu, Megumi, Taft, Ryan J., Antonellis, Anthony, and Hou, Ya-Ming more...
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ALANYL-trna synthetase , *GENETIC mutation , *PEOPLE with epilepsy , *AMINOACYL-tRNA , *MYELINATION , *LEUKODYSTROPHY - Abstract
Mutations in genes encoding aminoacyl-tRNA synthetases are known to cause leukodystrophies and genetic leukoencephalopathies—heritable disorders that result in white matter abnormalities in the central nervous system. Here we report three individuals (two siblings and an unrelated individual) with severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination on MRI. Analysis by whole exome sequencing identified mutations in the nuclear-encoded alanyl-tRNA synthetase ( AARS ) in these two unrelated families: the two affected siblings are compound heterozygous for p.Lys81Thr and p.Arg751Gly AARS , and the single affected child is homozygous for p.Arg751Gly AARS . The two identified mutations were found to result in a significant reduction in function. Mutations in AARS were previously associated with an autosomal-dominant inherited form of axonal neuropathy, Charcot-Marie-Tooth disease type 2N (CMT2N). The autosomal-recessive AARS mutations identified in the individuals described here, however, cause a severe infantile epileptic encephalopathy with a central myelin defect and peripheral neuropathy, demonstrating that defects of alanyl-tRNA charging can result in a wide spectrum of disease manifestations. [ABSTRACT FROM AUTHOR] more...
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- 2015
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12. An assessment of mechanisms underlying peripheral axonal degeneration caused by aminoacyl-tRNA synthetase mutations
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Stum, Morgane, McLaughlin, Heather M., Kleinbrink, Erica L., Miers, Kathy E., Ackerman, Susan L., Seburn, Kevin L., Antonellis, Anthony, and Burgess, Robert W.
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AMINOACYL-tRNA synthetases , *GENETIC mutation , *DENTAL pathology , *NEURODEGENERATION , *EMBRYONIC stem cells , *AMINO acids , *ACYLATION , *NEUROPATHY - Abstract
Abstract: Mutations in glycyl-, tyrosyl-, and alanyl-tRNA synthetases (GARS, YARS and AARS respectively) cause autosomal dominant Charcot–Marie–Tooth disease, and mutations in Gars cause a similar peripheral neuropathy in mice. Aminoacyl-tRNA synthetases (ARSs) charge amino acids onto their cognate tRNAs during translation; however, the pathological mechanism(s) of ARS mutations remains unclear. To address this, we tested possible mechanisms using mouse models. First, amino acid mischarging was discounted by examining the recessive “sticky” mutation in alanyl-tRNA synthetase (Aars sti ), which causes cerebellar neurodegeneration through a failure to efficiently correct mischarging of tRNAAla. Aars sti/sti mice do not have peripheral neuropathy, and they share no phenotypic features with the Gars mutant mice. Next, we determined that the Wallerian Degeneration Slow (Wlds) mutation did not alter the Gars phenotype. Therefore, no evidence for misfolding of GARS itself or other proteins was found. Similarly, there were no indications of general insufficiencies in protein synthesis caused by Gars mutations based on yeast complementation assays. Mutant GARS localized differently than wild type GARS in transfected cells, but a similar distribution was not observed in motor neurons derived from wild type mouse ES cells, and there was no evidence for abnormal GARS distribution in mouse tissue. Both GARS and YARS proteins were present in sciatic axons and Schwann cells from Gars mutant and control mice, consistent with a direct role for tRNA synthetases in peripheral nerves. Unless defects in translation are in some way restricted to peripheral axons, as suggested by the axonal localization of GARS and YARS, we conclude that mutations in tRNA synthetases are not causing peripheral neuropathy through amino acid mischarging or through a defect in their known function in translation. [Copyright &y& Elsevier] more...
- Published
- 2011
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